Use of nicotinic acetylcholine receptor alpha 7 activators

ABSTRACT

The invention concerns the use of a nicotinic acetylcholine receptor alpha 7 activators for the treatment, prevention or delay of progression of dyskinesia associated with dopamine agonist therapy in Parkinson&#39;s Disease.

CROSS-REFERENCE TO RELATED PATENT APPLICATIONS

This application is a National Stage of International Application No.PCT/EP2010/063946, filed Sep. 22, 2010, which is based upon and claimsthe benefit of priority from prior U.S. Provisional Patent ApplicationNo. 61/244,658, filed Sep. 22, 2009, the entire contents of all of whichare incorporated herein by reference in their entirety.

The present invention relates to pharmaceutical uses of nicotinicacetylcholine receptor alpha 7 (α7-nAChR) activators, i.e. α7-nAChRagonists or positive allosteric modulators.

Parkinson's Disease (PD) is a chronic and progressive degenerativedisorder of the central nervous system that often impairs the sufferer'smotor skills and speech. Characteristics of Parkinson's Disease arevaried and include one or more of the following: tremor, rigidity,bradykinesia, akinesia, gait and postural disturbances, posturalinstability, speech and swallowing disturbances and cognitive impairment(e.g. memory loss, dementia and slowed reaction times). PD is thought tobe the direct result of the loss of dopamine-producing cells in thesubstantia nigra. More than 60,000 new cases of PD are diagnosed in theUSA alone each year.

The most commonly used treatment for PD is dopamine agonist therapy, forexample by administration of L-dopa (levodopa) in combination with adecarboxylase inhibitor (e.g. carbidopa). However, for many patients, along term dopamine agonist therapy causes involuntary movements(dyskinesias) as a significant side effect (for review: Fabbrini et al,Movement Disorders, 2007, 22(10), 1379-1389; Konitsiotis, Expert OpinInvestig Drugs, 2005, 14(4), 377-392; Brown et al, (Drugs, 2002, 5(5),454-468). Consequently, there is a need for effective regimes forinhibiting or treating dyskinesia, which can be carried out withoutadversely affecting anti-PD treatments.

Compounds described as α7-nAChR agonists or α7-nAChR positive allostericmodulators have been described in, e.g. WO2001/85727, WO2004/022556,WO2005/118535, WO2005/123732, WO2006/005608, WO2007/045478,WO2007/068476, WO2007/068475 and Haydar et al (Current Topics inMedicinal Chemistry, 2010, 10, 144-152).

It has been found that α7-nAChR agonists or α7-nAChR positive allostericmodulators may be used in the treatment, prevention or delay ofprogression of dyskinesia associated with dopamine agonist therapy inPD. In particular, it has been found that α7-nAChR agonists or α7-nAChRpositive allosteric modulators may be used in the treatment, preventionor delay of progression of said dyskinesia, wherein the therapycomprises the administration of levodopa.

Accordingly, a first aspect of the invention concerns the use of aα7-nAChR agonist or a α7-nAChR positive allosteric modulator for thetreatment (whether therapeutic or prophylactic), prevention or delay ofprogression of dyskinesia associated with dopamine agonist therapy inParkinson's Disease.

One embodiment of said first aspect concerns the use of a α7-nAChRagonist for the treatment (whether therapeutic or prophylactic),prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease.

Another embodiment of said first aspect concerns the use of a α7-nAChRpositive allosteric modulator for the treatment (whether therapeutic orprophylactic), prevention or delay of progression of dyskinesiaassociated with dopamine agonist therapy in Parkinson's Disease.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR agonist or a α7-nAChRpositive allosteric modulator.

One embodiment of said further aspect relates to a method for thetreatment, prevention or delay of progression of dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in a subject inneed of such treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR agonist.

Another embodiment of said further aspect relates to a method for thetreatment, prevention or delay of progression of dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in a subject inneed of such treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR positive allostericmodulator.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises (i) diagnosing dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in said subject and(ii) administering to said subject a therapeutically effective amount ofa α7-nAChR agonist or a α7-nAChR positive allosteric modulator.

One embodiment of said further aspect relates to a method for thetreatment, prevention or delay of progression of dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in a subject inneed of such treatment, which comprises (i) diagnosing dyskinesiaassociated with dopamine agonist therapy in Parkinson's Disease in saidsubject and (ii) administering to said subject a therapeuticallyeffective amount of a α7-nAChR agonist. Another embodiment of saidfurther aspect relates to a method for the treatment, prevention ordelay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease in a subject in need of such treatment,which comprises (i) diagnosing dyskinesia associated with dopamineagonist therapy in Parkinson's Disease in said subject and (ii)administering to said subject a therapeutically effective amount of aα7-nAChR positive allosteric modulator.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a α7-nAChR agonist or a α7-nAChR positiveallosteric modulator for the treatment, prevention or delay ofprogression of dyskinesia associated with dopamine agonist therapy inParkinson's Disease.

One embodiment of said further aspect relates to a pharmaceuticalcomposition comprising a α7-nAChR agonist or a α7-nAChR positiveallosteric modulator for the treatment, prevention or delay ofprogression of dyskinesia associated with dopamine agonist therapy inParkinson's Disease.

Another embodiment of said further aspect relates to a pharmaceuticalcomposition comprising a α7-nAChR agonist or a α7-nAChR positiveallosteric modulator for the treatment, prevention or delay ofprogression of dyskinesia associated with dopamine agonist therapy inParkinson's Disease.

A further aspect of the invention relates to the use of a α7-nAChRagonist or a α7-nAChR positive allosteric modulator for the manufactureof a medicament for the treatment, prevention or delay of progression ofdyskinesia associated with dopamine agonist therapy in Parkinson'sDisease.

One embodiment of said further aspect relates to the use of a α7-nAChRagonist for the manufacture of a medicament for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease.

Another embodiment of said further aspect relates to the use of aα7-nAChR positive allosteric modulator for the manufacture of amedicament for the treatment, prevention or delay of progression ofdyskinesia associated with dopamine agonist therapy in Parkinson'sDisease.

Nicotinic Acetylcholine Receptor Alpha 7 Agonist:

As used herein a “α7-nAChR agonist” is a compound that binds to areceptor comprising a α7-nAChR subunit in vivo and in vitro and isactivating the receptor to perform its physiological function.Activation can be measured by the method disclosed in WO2001/85727, i.e.a functional affinity assay at the homomeric alpha 7 nicotinicacetylcholine receptor (α7 nAChR) carried out with a rat pituitary cellline stably expressing the α7 nAChR. As read out, the calcium influxupon stimulation of the receptor compared to epibatidine is used.“α7-nAChR agonists” according to the invention typically induce calciuminflux of at least 50% of the maximal influx evoked by epibatidine withan EC₅₀ value of at least 1 μM; preferred agonists induce calcium influxof at least 75% of the maximal influx evoked by epibatidine with an EC₅₀value of at least 400 nM; more preferred agonists induce calcium influxof at least 85% of the maximal influx evoked by epibatidine with an EC₅₀value of at least 50 nM.

In particular, preferred α7-nAChR agonists should be well absorbed fromthe gastrointestinal tract, should be sufficiently metabolically stableand possess favorable pharmacokinetic properties.

Further preferred α7-nAChR agonists bind in-vivo potently to α7-nAChRswhilst showing little affinity for other receptors, especially for othernAChRs, e.g. α4β2 nAChR, for muscarinic acetylcholine receptors, e.g.M1, and/or the 5-HT₃ receptor.

Further preferred α7-nAChR agonists cross the blood brain barriereffectively.

Preferred α7-nAChR agonists should be non-toxic and demonstrate fewside-effects. Furthermore, a preferred α7-nAChR agonist will be able toexist in a physical form that is stable, non-hygroscopic and easilyformulated.

In one embodiment, the α7-nAChR agonist is selective for a receptorcomprising a α7-nAChR subunit, since such an agonist would be expectedto cause fewer side effects than a non-selective agonist to a treatedsubject. An agonist being selective for a receptor comprising a α7-nAChRsubunit has a functional affinity to such a receptor to a much higherdegree, e.g. at least 10-fold affinity difference in EC₅₀ value,preferably at least 20-fold, more preferably at least 50-fold, comparedto any other nicotinic acetylcholine receptor. To assess the affinity ofthe α7-nAChR agonists of the invention on other nicotinic acetylcholinereceptors, the method disclosed in WO2001/85727 can be used, i.e. toassess the affinity on human neuronal α4β2 nAChR, a similar functionalassay is carried out using a human embryonic kidney cell line stableexpressing the human α4β2 subtype and to assess the activity of thecompounds of the invention on the “ganglionic subtype” and the “muscletype” of nicotinic receptor, similar functional assays are carried outwith a human embryonic kidney cell line stably expressing the human“ganglionic subtype” or a cell line endogenously expressing the human“muscle type” of nicotinic receptors.

In the last 15 years much effort has been focused on developingselective α7 nAChR agonists leading to the discovery of many differentchemotypes displaying said selective activity. These efforts aresummarized the review from Horenstein et al (Mol Pharmacol, 2008, 74,1496-1511, which describes no less than 9 different families of α7 nAChRagonists, in most of which selective agonists have been found. Allcompounds disclosed in FIG. 1 of said review are incorporated herein byreference. In fact, several drug candidates having an α7 nAChR agonistmode of action entered pre-clinical or even clinical testing (forreview: Broad et al, Drugs of the Future, 2007, 32(2), 161-170;Romanelli et al, Expert Opin Ther Patents, 2007, 17(11), 1365-1377).Examples of such compounds—again belonging to a diversity ofchemotypes—are MEM3454, MEM63908, SSR180711, GTS21, EVP6124, ABT107,ABT126, TC-5619, AZD-6319 and SAR-130479. Further α7 nAChR agonists andtheir use as pharmaceuticals are known, for example, from WO2001/85727,WO2004/022556, WO2005/118535, WO2005/123732, WO2006/005608,WO2007/045478, WO2007/068476 and WO2007/068475.

In one embodiment, the α7-nAChR agonist is a compound of formula (I)

wherein

L₁ is —CH₂—; L₂ is —CH₂— or —CH₂—CH₂—; and L₃ is —CH₂— or —CH(CH₃)—; or

L₁ is —CH₂—CH₂—; L₂ is —CH₂—; and L₃ is —CH₂—CH₂—;

L₄ is a group selected from

wherein the bond marked with the asterisk is attached to theazabicycloalkyl moiety;

R₁ is hydrogen or C₁₋₄alkyl;

X₁ is —O— or —NH—;

A₂ is selected from

wherein the bond marked with the asterisk is attached to X₁;

A₁ is a five- to ten-membered monocyclic or fused polycyclic aromaticring system which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may contain notmore than 2 oxygen atoms and not more than 2 sulfur atoms, and whereinthe ring system may be substituted once or more than once by R₂, andwherein a substituent on a nitrogen in a heterocyclic ring system maynot be halogen;

each R₂ independently is C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy,C₁₋₆halogenalkoxy, halogen, cyano or a three- to six-membered monocyclicring system which may be aromatic, saturated or partially saturated andwhich may contain from 1 to 4 hetero atoms selected from nitrogen,oxygen and sulfur, and wherein each ring system may contain not morethan 2 oxygen atoms and not more than 2 sulfur atoms, and wherein eachring system may in turn be substituted once or more than once byC₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy, halogen orcyano, and wherein a substituent on a nitrogen in a heterocyclic ringsystem may not be halogen;

or two R₂ at adjacent ring atoms form a C₃₋₄alkylene group, wherein 1-2carbon atoms may be replaced by X₂, and wherein the C₃₋₄alkylene groupmay be substituted once or more than once by R₃;

each X₂ independently is —O— or —N(R₄)—;

each R₄ independently is hydrogen or C₁₋₆alkyl; and

each R₃ independently is halogen or C₁₋₆alkyl;

in free base form or in acid addition salt form.

In one embodiment, the α7-nAChR agonist is a compound of formula (II)

wherein

A₃ is a five- to ten-membered monocyclic or fused polycyclic aromaticring system which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may contain notmore than 2 oxygen atoms and not more than 2 sulfur atoms, and whereinthe ring system may be substituted once or more than once by R₅, andwherein a substituent on a nitrogen in a heterocyclic ring system maynot be halogen;

each R₅ independently is C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy,C₁₋₆halogenalkoxy, halogen, cyano, amino or a three- to six-memberedmonocyclic ring system which may be aromatic, saturated or partiallysaturated and which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, and wherein each ring system may containnot more than 2 oxygen atoms and not more than 2 sulfur atoms, andwherein each ring system may in turn be substituted once or more thanonce by C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy, C₁₋₆halogenalkoxy,halogen or cyano, and wherein a substituent on a nitrogen in aheterocyclic ring system may not be halogen;

or two R₅ at adjacent ring atoms form a C₃₋₄alkylene group, wherein 1-2carbon atoms may be replaced by X₃, and wherein the C₃₋₄alkylene groupmay be substituted once or more than once by R₆;

each X₃ independently is —O— or —N(R₇)—;

each R₇ independently is hydrogen or C₁₋₆alkyl; and

each R₆ independently is halogen or C₁₋₆alkyl;

in free base form or in acid addition salt form.

Unless indicated otherwise, the expressions used in this invention havethe following meaning:

“Alkyl” represents a straight-chain or branched-chain alkyl group, forexample, methyl, ethyl, n- or iso-propyl, n-, iso-, sec- or tert-butyl,n-pentyl, n-hexyl; C₁₋₆alkyl preferably represents a straight-chain orbranched-chain C₁₋₄alkyl with particular preference given to methyl,ethyl, n-propyl, iso-propyl and tert-butyl.

Each alkyl part of “alkoxy”, “halogenalkyl” and so on shall have thesame meaning as described in the above-mentioned definition of “alkyl”,especially regarding linearity and preferential size.

A substituent being substituted “once or more than once”, for example asdefined for A₁, is preferably substituted by one to three substituents.

Halogen is generally fluorine, chlorine, bromine or iodine; preferablyfluorine, chlorine or bromine. Halogenalkyl groups preferably have achain length of 1 to 4 carbon atoms and are, for example, fluoromethyl,difluoromethyl, trifluoromethyl, chloromethyl, dichloromethyl,trichloromethyl, 2,2,2-trifluoroethyl, 2-fluoroethyl, 2-chloroethyl,pentafluoroethyl, 1,1-difluoro-2,2,2-trichloroethyl,2,2,2-trichloroethyl, 1,1,2,2-tetrafluoroethyl,2,2,3,3-tetrafluoropropyl, 2,2,3,3,3-pentafluoropropyl or2,2,3,4,4,4-hexafluorobutyl; preferably —CF₃, —CHF₂, —CH₂F, —CHF—CH₃,—CF₂CH₃, or —CH₂CF₃.

In the context of the invention, the definitions of “two R₂ at adjacentring atoms form a C₃₋₄alkylene group, wherein 1-2 carbon atoms may bereplaced by X₂” or “two R₅ at adjacent ring atoms form a C₃₋₄alkylenegroup, wherein 1-2 carbon atoms may be replaced by X₃” encompass—CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—, —O—CH₂—O—, —O—CH₂—CH₂—O— and—CH₂—CH₂—NH—. An example of a substituted group is —CH₂—CH₂—N(CH₃)—.

In the context of the invention, the definition of A₁ or A₃ as a “five-to ten-membered monocyclic or fused polycyclic aromatic ring system”encompasses a C₆- or C₁₀-aromatic hydrocarbon group or a five- toten-membered heterocyclic aromatic ring system. “Polycyclic” meanspreferably bicyclic.

In the context of the invention, the definition of R₂ as a “three- tosix-membered monocyclic ring system” encompasses a C₆-aromatichydrocarbon group, a five- to six-membered heterocyclic aromatic ringsystem and a three- to six-membered monocydic aliphatic or heterocyclicring system.

A C₆- or C₁₀-aromatic hydrocarbon group is typically phenyl or naphthyl,especially phenyl.

Preferably, but also depending on substituent definition, “five- toten-membered heterocyclic aromatic ring systems” consist of 5 to 10 ringatoms of which 1-3 ring atoms are hetero atoms. Such heterocyclicaromatic ring systems may be present as a single ring system or asbicyclic or tricyclic ring systems; preferably as single ring systems oras benz-annelated ring systems. Bicyclic or tricyclic ring systems maybe formed by annelation of two or more rings, or by a bridging atom,e.g. oxygen, sulfur, nitrogen. Examples of heterocyclic ring systemsare: imidazo[2,1-b]thiazole, pyrrole, pyrroline, pyrrolidine, pyrazole,pyrazoline, pyrazolidine, imidazole, imidazoline, imidazolidine,triazole, triazoline, triazolidine, tetrazole, furane, dihydrofurane,tetrahydrofurane, furazane (oxadiazole), dioxolane, thiophene,dihydrothiophene, tetrahydrothiophene, oxazole, oxazoline, oxazolidine,isoxazole, isoxazoline, isoxazolidine, thiazole, thiazoline,thiazolidine, isothiazole, isothiazoline, isothiazolidine, thiadiazole,thiadiazoline, thiadiazolidine, pyridine, piperidine, pyridazine,pyrazine, piperazine, triazine, pyrane, tetrahydropyrane, thiopyrane,tetrahydrothiopyrane, oxazine, thiazine, dioxine, morpholine, purine,pteridine, and the corresponding benz-annelated heterocycles, e.g.indole, isoindole, coumarin, isoquinoline, quinoline and the like.Preferred heterocycles are: imidazo[2,1-b]thiazole, oxazole, isoxazole,thiazole, isothiazole, triazole, pyrrole, furane, tetrahydrofurane,pyridine, pyrimidine, imidazole or pyrazole.

In the context of the invention, three- to six-membered monocyclicaliphatic ring systems are typically cyclopropyl, cyclobutyl,cyclopentyl or cyclohexyl.

On account of asymmetrical carbon atom(s) that may be present in thecompounds of formula (I) and compounds of formula (II), the compoundsmay exist in optically active form or in form of mixtures of opticalisomers, e.g. in form of racemic mixtures or diastereomeric mixtures.All optical isomers and their mixtures, including racemic mixtures, arepart of the present invention.

In one embodiment, the α7-nAChR agonist is a compound of formula (I)

wherein

L₁ is —CH₂—; L₂ is —CH₂—CH₂—; and L₃ is —CH₂— or —CH(CH₃)—;

L₄ is a group selected from

wherein the bond marked with the asterisk is attached to theazabicycloalkyl moiety;

R₁ is hydrogen or C₁₋₄alkyl;

X₁ is —O— or —NH—;

A₂ is selected from

wherein the bond marked with the asterisk is attached to X₁;

A₁ is a five- to ten-membered monocyclic or fused polycyclic aromaticring system which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may contain notmore than 2 oxygen atoms and not more than 2 sulfur atoms, and whereinthe ring system may be substituted once or more than once by R₂, andwherein a substituent on a nitrogen in a heterocyclic ring system maynot be halogen; and

each R₂ independently is C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy,C₁₋₆halogenalkoxy or halogen.

In one embodiment, the α7-nAChR agonist is a compound of formula (I)

wherein

L₁ is —CH₂—; L₂ is —CH₂—CH₂—; and L₃ is —CH₂—;

L₄ is

wherein the bond marked with the asterisk is attached to theazabicycloalkyl moiety;

R₁ is hydrogen or C₁₋₄alkyl;

A₁ is a five- to ten-membered monocyclic or fused polycyclic aromaticring system which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may contain notmore than 2 oxygen atoms and not more than 2 sulfur atoms, and whereinthe ring system may be substituted once or more than once by R₂, andwherein a substituent on a nitrogen in a heterocyclic ring system maynot be halogen; and

each R₂ independently is C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy,C₁₋₆halogenalkoxy or halogen.

In one embodiment, the α7-nAChR agonist is a compound of formula (I)

wherein

L₁ is —CH₂—; L₂ is —CH₂—CH₂—; and L₃ is —CH₂— or —CH(CH₃)—;

L₄ is

wherein the bond marked with the asterisk is attached to theazabicycloalkyl moiety;

X₁ is —O— or —NH—;

A₂ is selected from

wherein the bond marked with the asterisk is attached to X₁;

A₁ is a five- to ten-membered monocyclic or fused polycyclic aromaticring system which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may contain notmore than 2 oxygen atoms and not more than 2 sulfur atoms, and whereinthe ring system may be substituted once or more than once by R₂, andwherein a substituent on a nitrogen in a heterocyclic ring system maynot be halogen; and

each R₂ independently is C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy,C₁₋₆halogenalkoxy or halogen.

In one embodiment, the α7-nAChR agonist is a compound of formula (I)

wherein

L₁ is —CH₂—CH₂—, L₂ is —CH₂—, and L₃ is —CH₂—CH₂—;

L₄ is

wherein the bond marked with the asterisk is attached to theazabicycloalkyl moiety;

X₁ is —O— or —NH—;

A₂ is selected from

wherein the bond marked with the asterisk is attached to X₁;

A₁ is a five- to ten-membered monocyclic or fused polycyclic aromaticring system which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may contain notmore than 2 oxygen atoms and not more than 2 sulfur atoms, and whereinthe ring system may be substituted once or more than once by R₂, andwherein a substituent on a nitrogen in a heterocyclic ring system maynot be halogen; and

each R₂ independently is C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy,C₁₋₆halogenalkoxy or halogen.

In one embodiment, the α7-nAChR agonist is a compound of formula (II)

wherein

A₃ is a five- to ten-membered monocyclic or fused polycyclic aromaticring system which may contain from 1 to 4 hetero atoms selected fromnitrogen, oxygen and sulfur, wherein the ring system may contain notmore than 2 oxygen atoms and not more than 2 sulfur atoms, and whereinthe ring system may be substituted once or more than once by R₅, andwherein a substituent on a nitrogen in a heterocyclic ring system maynot be halogen; and

each R₅ independently is C₁₋₆alkyl, C₁₋₆halogenalkyl, C₁₋₆alkoxy,C₁₋₆halogenalkoxy, amino or halogen.

In one embodiment, the α7-nAChR agonist is a compound selected fromGroup P1; Group P1 is the group consisting of

-   A-1: (S)-(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid    (S)-1-(2-fluoro-phenyl)-ethyl ester;-   A-2: (R)-(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid    (R)-1-(2-chloro-phenyl)-ethyl ester;-   A-3: (S)-(1-aza-bicyclo[2.2.2]oct-3-yl)-carbamic acid    (S)-1-phenyl-ethyl ester;-   B-1: (R)-3-(5-phenyl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;-   B-2: (R)-3-(5-p-tolyl-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;-   B-3:    (R)-3-(5-(2-fluoro-4-methyl-phenyl)-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;-   B-4:    (R)-3-(5-(3,4-dimethyl-phenyl)-pyrimidin-2-yloxy)-1-aza-bicyclo[2.2.2]octane;-   B-5: (R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;-   B-6: (R)-3-(6-phenyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;-   B-7:    (R)-3-(6-(3,4-dimethyl-phenyl)-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane;-   B-8:    (R)-3-[6-(2-fluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;-   B-9:    (R)-3-[6-(4,5-dimethyl-2-fluoro-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;-   B-10:    (R)-3-[6-(3,4-dimethyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;-   B-11:    (R)-3-[6-(4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;-   B-12:    (R)-3-[6-(2,5-difluoro-4-methyl-phenyl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;-   B-13:    (2S,3R)-3-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;-   B-14:    (2R,3S)-3-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;-   B-15:    (2S,3R)-3-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;-   B-16:    (2R,3S)-3-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;-   B-17:    3-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;-   B-18:    (2S,3R)-2-methyl-3-[6-(5-methyl-thiophen-2-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[2.2.2]octane;-   B-19:    3-[6-(2,3-dimethyl-1H-indol-5-yl)-pyridazin-3-yloxy]-2-methyl-1-aza-bicyclo[2.2.2]octane;-   B-20:    trans-2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-(6-phenyl-pyridin-3-yl)-amine;-   B-21:    trans-[6-(1H-indol-5-yl)-pyridin-3-yl]-(2-methyl-1-aza-bicyclo[2.2.2]oct-3-yl)-amine;-   C-1:    (4S,5R)-4-[5-(1H-indol-5-yl)-pyrimidin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane;-   C-2:    5-{2-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyrimidin-5-yl}-1,3-dihydro-indol-2-one;-   C-3:    (4S,5R)-4-[6-(1H-indol-5-yl)-pyridin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane;-   C-4:    (4S,5R)-4-[5-(1H-indol-5-yl)-pyridin-2-yloxy]-1-aza-bicyclo[3.3.1]nonane;-   C-5:    (4S,5R)-4-[6-(1H-indol-5-yl)-pyridazin-3-yloxy]-1-aza-bicyclo[3.3.1]nonane;-   C-6:    5-{6-[(4S,5R)-(1-aza-bicyclo[3.3.1]non-4-yl)oxy]-pyridazin-3-yl}-1,3-dihydro-indol-2-one;-   C-7:    (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyridin-2-yl]-amine;-   C-8:    (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-5-yl)-pyrimidin-2-yl]-amine;-   C-9:    (1-aza-bicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridin-3-yl]-amine;-   C-10:    (1-aza-bicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridin-3-yl]amine;-   C-11:    (1-aza-bicyclo[3.3.1]non-4-yl)-[5-(1H-indol-4-yl)-pyrimidin-2-yl]-amine;-   C-12:    (1-aza-bicyclo[3.3.1]non-4-yl)-[6-(1H-indol-5-yl)-pyridazin-3-yl]-amine;-   D-1:    5-benzofuran-5-ylethynyl-1-methyl-3-piperidin-1-ylmethyl-pyrrolidin-2-one;-   D-2:    1-methyl-5-phenylethynyl-3-piperidin-1-ylmethyl-pyrrolidin-2-one;-   D-3:    1-methyl-5-(1-methyl-1H-indol-5-ylethynyl)-3-piperidin-1-ylmethyl-pyrrolidin-2-one;-   D-4:    5-(3-Amino-phenylethynyl)-1-methyl-3-piperidin-1-ylmethyl-pyrrolidin-2-one;-   E-1:    4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3.3.1.1^(3,7)]decane    having the formula

-   E-1a:    (4S)-4-(5-phenyl-1,3,4-thiadiazol-2-yloxy)-1azatricyclo[3.3.1.1^(3,7)]decane;-   E-1b:    4-(6-(1H-indol-5-yl)-pyridazin-3-yloxy)-1azatricyclo[3.3.1.1^(3,7)]decane;-   E-1c: 4-(6-(1H-indol-5-yl)-pyridin-3-yloxy)-1    azatricyclo[3.3.1.1^(3,7)]decane;-   E-1d: 4-(5-(1H-indol-5-yl)-pyrimidin-2-yloxy)-1    azatricyclo[3.3.1.1^(3,7)]decane;-   E-2: 2-(6-phenylpyridazine-3-yl)octahydropyrrolo[3,4-c]pyrrole    having the formula

-   E-3:    5-[6-(5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-pyridazin-3-yl1H-indole    having the formula

-   E-3a:    5-[6-(cis-5-methyl-hexahydro-pyrrolo[3,4-c]pyrrol-2-yl-pyridazin-3-yl1H-indole;-   E-4:    5-[5-{6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl}-pyridin-2-yl]-1H-indole    having the formula

-   E-4a:    5-[5-{(1R,5R)-6-methyl-3,6-diaza-bicyclo[3.2.0]hept-3-yl}-pyridin-2-yl]-1H-indole-   E-5:    2-Methyl-5-(6-phenyl-pyridazin-3-yl)-octahydro-pyrrolo[3,4-c]pyrrole    having the formula

-   E-6: 5-{6-[1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;-   E-6a:    5-{6-[(3R)-1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1H-indole;-   E-7:    5-{6-[1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1,3-dihydro-indol-2-one;-   E-7a:    5-{6-[(3R)1-azabicyclo[2.2.2]oct-3-yloxy]pyridazin-3-yl}-1,3-dihydro-indol-2-one;-   E-8: N-(1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide;-   E-8a: N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide-   E-8b: N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-1H-indazole-3-carboxamide-   E-9:    N-(1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;-   E-9a:    N-((3R)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;-   E-9b:    N-((3S)-1-azabicyclo[2.2.2]oct-3-yl)-5-(trifluoromethoxy)-1H-indazole-3-carboxamide;-   E-10:    N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;-   E-10a:    (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)benzofuran-2-carboxamide;-   E-11:    N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;-   E-11a:    (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-3,5-difluorobenzamide;-   E-11b:    N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;-   E-11c:    (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-methylthiophene-2-carboxamide;-   E-11d:    N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;-   E-11e:    (2S,3R)—N-(2-((3-pyridinyl)methyl)-1-azabicyclo[2.2.2]oct-3-yl)-5-(2-pyridinyl)thiophene-2-carboxamide;-   E-12:    4-(5-methyloxazolo[4,5-b]pyridin-2-yl)-1,4-diazabicyclo[3.2.2]nonane;-   E-13: [N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-4-chlorobenzamide;-   E-14: furo[2,3-c]pyridine-5-carboxylic acid    (1-aza-bicyclo[2.2.2]oct-3-yl)amide;-   E-15: 2,3-dihydro-benzo[1,4]dioxine-6-carboxylic acid    (1-aza-bicyclo[2.2.2]oct-3-yl)-amide;-   E-16: 5-morpholin-4-yl-pentanoic acid (4-pyridin-3-yl-phenyl)-amide;-   E-17:    N-{4-[4-(2,4-dimethoxy-phenyl)-piperazin-1-yl]-butyl}-4-pyridin-2-yl-benzamide;-   E-18:    1-[6-(4-fluorophenyl)pyridin-3-yl]-3-(4-piperidin-1-ylbutyl)-urea;-   E-19:    7,8,9,10-tetrahydro-6,10-methano-6H-pyrazino-(2,3-h)(3)-benzazepine;-   E-20:    (2′R)-spiro-[1-azabicyclo[2.2.2]octane-3,2′(3′H)-furo[2,3-b]pyridine];-   E-21: 1,4-Diaza-bicyclo[3.2.2]nonane-4-carboxylic acid    4-bromo-phenyl ester;-   E-22:    3-[1-(2,4-Dimethoxy-phenyl)-meth-(E)-ylidene]-3,4,5,6-tetrahydro-[2,3′]bipyridinyl;-   E-23: 7-(2-Methoxy-phenyl)-benzofuran-2-carboxylic acid    (1-aza-bicyclo[2.2.2]oct-3-yl)-amide;-   E-24:    N-methyl-1-{5-[3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine    having the formula

-   E-24a:    N-methyl-1-{5-[(2R)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;-   E-24b:    N-methyl-1-{5-[(2S)-3′H-spiro[4-azabicyclo[2.2.2]octane-2,2′-furo[2,3-b]pyridin]-5′-yl]-2-thienyl}methanamine;-   E-25a:    6-[(Anilinocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide;-   E-25b: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-chlorophenyl)    amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;-   E-25c:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;-   E-25d:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;-   E-25e:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-phenylethyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;-   E-25f:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-cyanophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;-   E-25g:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3-bromophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;-   E-25h:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-ethoxyphenyl)amino]carbonyl)amino)-1-benzothiophene-2-carboxamide;-   E-25i:    N-[(3R)-1-Azbicyclo[2.2.2]oct-3-yl]-6-({[(4-(dimethylamino)phenyl)amino]-carbonyl)amino)-1-benzothiophene-2-carboxamide;-   E-25j:    N-(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2-nitrophenyl)amino]carbonyl}amino)-1-benzothiophene-2-carboxamide;-   E-25k:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,6-difluorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;-   E-25l:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(2,4-dichlorophenyl)amino]carbonyl}-amino)-1-benzothiophene-2-carboxamide;-   E-25m:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-(trifluoromethyl)phenyl]amino]-carbonyl)amino}-1-benzothiophene-2-carboxamide;-   E-25n:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(3,4,5-trimethoxyphenyl)amino]-carbonyl}amino)-1-benzothiophene-2-carboxamide;-   E-25o:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[4-methoxy-3-(trifluoromethyl)phenyl]-amino}carbonyl)amino]-1-benzothiophene-2-carboxamide;-   E-25p:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-methoxyphenyl]amino}carbonyl)-amino]-1-benzothiophene-2-carboxamide;-   E-25q:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[3-trifluoromethoxyphenyl]amino}-carbonyl)-amino]-1-benzothiophene-2-carboxamide;-   E-25r:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(tert-butylamino)carbonyl]amino}-1-benzothiophene-2-carboxamide;-   E-25s:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-{[(cyclohexylamino)carbonyl]amino}-1-benzothiophene-2-carboxamide;-   E-25t:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-[({[(1S)-1-phenylethyl]amino}carbonyl-amino]-1-benzothiophene-2-carboxamide;-   E-25u:    7-[(Anilinocarbonyl)amino]-N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-1-benzothiophene-2-carboxamide;-   E-25v:    N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-({[(4-methoxyphenyl)amino]carbonyl}-amino)-1-benzofuran-2-carboxamide;-   E-26a:    N-[4-(2-Thienyl)phenyl]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26b:    N-[4′-(Hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26c:    N-(4′-Fluoro-1,1′-biphenyl-4-yl)-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26d:    N-(4′-Methylsulfanyl-1,1′-biphenyl-4-yl)-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26e:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(4′-fluoro-1,1′-biphenyl-4-yl)acetamide;-   E-26f:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(4′-methoxy-1,1′-biphenyl-4-yl)acetamide;-   E-26g:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(4′-fluoro-1,1′-biphenyl-3-yl)acetamide;-   E-26h:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(3′-nitro-1,1′-biphenyl-4-yl)acetamide;-   E-26i:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-[4′-(hydroxymethyl)-1,1′-biphenyl-3-yl]acetamide;-   E-26j:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-[4′-(bromomethyl)-1,1′-biphenyl-4-yl]acetamide;-   E-26k:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-[2′-(hydroxymethyl)-1,1′-biphenyl-3-yl]acetamide;-   E-26l:    N-[3′(Acetylamino)-1,1′-biphenyl-4-yl]-2-(1-azabicyclo[2.2.2]oct-3-yl)acetamide;-   E-26m:    (3R)—N-[2′-(Hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26n:    (3R)—N-[4′-(Hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26o:    (3S)—N-[4′(Hydroxymethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26p:    (3R)—N-[4′-(4-Morpholinyl)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26q:    (3R)—N-[4′-(Hydroxymethyl)-3′-(methoxy)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]-octane-3-carboxamide;-   E-26r: Methyl    4′-{[(3S)-1-azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1′-biphenyl-4-carboxylate;-   E-26s:    4′-{[(3S)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1′-biphenyl-4-carboxylic    Acid;-   E-26t:    (3R)—N-[4′-(Hydroxy-1-methylethyl)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]-octane-3-carboxamide;-   E-26u:    (3R)—N-[4′-(Aminocarbonyl)-1,1′-biphenyl-4-yl]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26v:    (3R)—N-[4′-(Hydroxymethyl)-3-fluoro-1,1′-biphenyl-4-0]-1-azabicyclo[2.2.2]octane-3-carboxamide;-   E-26w:    (4′-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1′-biphenyl-4-yl)methyl    Methylcarbamate;-   E-26x:    (4′-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1′-biphenyl-4-yl)methyl    isopropylcarbamate;-   E-26y:    (4′-{[(3R)-1-Azabicyclo[2.2.2]oct-3-ylcarbonyl]amino}-1,1′-biphenyl-4-yl)methyl    Ethylcarbamate;-   E-26z: the free base form of a compound being selected from Examples    No 26, 27, 28, 29, 30, 31, 32, 33, 34 and 35 of WO2003/078431;-   E-27a:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(7-bromo-1-benzothien-2-yl)acetamide;-   E-27b:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(6-bromo-1-benzothien-2-yl)acetamide;-   E-27c: 2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(7-quinolinyl)acetamide;-   E-27d: 2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(2-naphthyl)acetamide;-   E-27e:    2-(1-Azabicyclo[2.2.2]oct-3-yl)-N-(8-nitro-2-naphthyl)acetamide;-   E-28a: N-(1-Azabicyclo[2.2.2]oct-3-yl)-6-quinolinecarboxamide;-   E-28b: N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenazinecarboxamide;-   E-28c: N-(1-Azabicyclo[2.2.2]oct-3-yl)-7-quinolinecarboxamide;-   E-28d: N-[(3R)-1-Azabicyclo[2.2.2]oct-3-yl]-6-quinolinecarboxamide;-   E-28e:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-7-quinolinecarboxamide;-   E-28f:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-6-quinolinecarboxamide;-   E-28g:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methyl-7-quinolinecarboxamide;-   E-28h:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-methyl-6-quinoliecarboxamide;-   E-28i:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-methyl-6-quinolinecarboxamide;-   E-28j:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-propyl-6-quinolinecarboxamide;-   E-28k:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-6-quinolinecarboxamide;-   E-28l:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-propyl-7-quinolinecarboxamide;-   E-28m:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-ethyl-4-methyl-7-quinolinecarboxamide;-   E-28n:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-6-quinoline-carboxamide;-   E-28o:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-4-(tetrahydro-2H-pyran-2-yl)-7-quinoline-carboxamide;-   E-28p:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenyl-6-quinolinecarboxamide; and-   E-28q:    N-(1-Azabicyclo[2.2.2]oct-3-yl)-2-phenyl-7-quinolinecarboxamide;

wherein each of said compound is in free base form or in acid additionsalt form.

In one embodiment, the α7-nAChR agonist is a compound selected from thegroup consisting of compound A-1, A-2 and A-3; wherein each of saidcompound is in free base form or in acid addition salt form.

In one embodiment, the α7-nAChR agonist is a compound selected from thegroup consisting of compound B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8,B-9, B-10, B-11, B-12, B-13, B-14, B-15, B-16, B-17, B-18, B-19, B-20and B-21; wherein each of said compound is in free base form or in acidaddition salt form.

In one embodiment, the α7-nAChR agonist is a compound selected from thegroup consisting of compound C-1, C-2, C-3, C-4, C-5, C-6, C-7, C-8,C-9, C-10, C-11 and C-12; wherein each of said compound is in free baseform or in acid addition salt form.

In one embodiment, the α7-nAChR agonist is a compound selected from thegroup consisting of compound D-1, D-2, D-3 and D-4; wherein each of saidcompound is in free base form or in acid addition salt form.

In one embodiment, the α7-nAChR agonist is a compound selected fromGroup P2; Group P2 is the group consisting of compounds A-1, A-2, A-3,B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13,B-14, B-15, B-16, B-17, B-18, B-19, B-20, B-21, C-1, C-2, C-3, C-4, C-5,C-6, C-7, C-8, C-9, C-10, C-11, C-12, E-1, E-1a, E-1b, E-1c, E-1d, E-2,E-3, E-3a, E-4, E-4a, E-8, E-8a, E-8b, E-9, E-9a, E-9b, E-10, E-10a,E-11, E-11a, E-11b, E-11c, E-11d, E-11e, E-12, E-19, E-22, E-24, E-24a,E-24b, E-25a, E-25b, E-25c, E-25d, E-25e, E-25f, E-25g, E-25h, E-25i,E-25j, E-25k, E-25l, E-25m, E-25n, E-25o, E-25p, E-25q, E-25r, E-255,E-25t, E-25u, E-25v, E-28a, E-28b, E-28c, E-28d, E-28e, E-28f, E-28g,E-28h, E-28i, E-28j, E-28k, E-28l, E-28m, E-28n, E-28o, E-28p and E-28q;wherein each of said compound is in free base form or in acid additionsalt form.

In one embodiment, the α7-nAChR agonist is a compound selected fromGroup P3; Group P3 is the group consisting of compounds A-1, A-2, A-3,B-1, B-2, B-3, B-4, B-5, B-6, B-7, B-8, B-9, B-10, B-11, B-12, B-13,B-14, B-15, B-16, B-17, B-18, B-19, B-20, B-21, C-1, C-2, C-3, C-4, C-5,C-6, C-7, C-8, C-9, C-10, C-11, C-12, E-1, E-1a, E-1b, E-1c, E-1d, E-2,E-3, E-3a, E-4, E-4a, E-8, E-8a, E-8b, E-9, E-9a, E-9b, E-10, E-10a,E-11, E-11a, E-12, E-19, E-22, E-24, E-24a and E-24b; wherein each ofsaid compound is in free base form or in acid addition salt form.

The compounds of formula (I) (e.g. compounds A-1 to A-3, B-1 to B-21 andC-1 to C-12) or compounds of formula (II) (e.g. compounds D-1 to D-4)and their manufacture are known from WO2001/85727, WO2004/022556,WO2005/118535, WO2005/123732, WO2006/005608, WO2007/045478,WO2007/068476 and WO2007/068475, or can be prepared analogously to saidreferences.

Compounds E-1 and E-1a can be prepared according to WO2008/058096.

Compounds E-2, E-3, E-3a, E-4, E-4a and E-5 (A-582941) can be preparedaccording to WO2005/028477.

Compounds E-6, E-6a, E-7 and E7a can be prepared according toWO2006/065233 and/or WO2007/018738.

Compounds E-8, E-8a, E-8b, E-9, E-9a and E-9b can be prepared accordingto WO2004/029050 and/or WO2010/043515.

Compounds E-10 and E-10a can be prepared according to WO2004/076449and/or WO2009/018505;

Compounds E-11, E-11a to E-11e can be prepared according toWO2004/076449 and/or WO2010/085724 and/or WO2010/056622;

Compounds E-12 (CP-810123) and Compound E-19 (varenidine) are describedin O'Donnell et al, J Med Chem, 2010, 53, 1222-1237.

Compounds E-13 (PNU-282987), E-14 (PHA543613), E-21 (SSR-180771) andE-23 (ABBF) are described in Horenstein et al, Mol Pharmacol, 2008, 74,1496-1511.

Compounds E-15 (PHA568487), E-16 (WAY-317538), E-17 (WAY-264620), E-20(AZD-0328) and E-22 (GTS-21) are described in Haydar et al, CurrentTopics in Medicinal Chemistry, 2010, 10, 144-152.

Compound E-18 (WYE-103914) is described in Ghiron et al, J Med Chem,2010, 53, 4379-4389.

Compound E-24, E-24a and E-24b are described in WO2007/133155 and/orWO2009/066107.

Compounds E-25a to E-25v are described in WO2004/013136.

Compounds E-26a to E-26z are described in WO2003/078431.

Compounds E-27a to E-27e are described in WO2003/078430.

Compounds E-28a to E-28q are described in WO2003/043991.

A further aspect of the invention concerns the use of a α7-nAChR agonistfor the treatment (whether therapeutic or prophylactic), prevention ordelay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound of formula (I).

A further aspect of the invention concerns the use of a α7-nAChR agonistfor the treatment (whether therapeutic or prophylactic), prevention ordelay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound selected from the Group P1.

A further aspect of the invention concerns the use of a α7-nAChR agonistfor the treatment (whether therapeutic or prophylactic), prevention ordelay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound selected from the Group P2.

A further aspect of the invention concerns the use of a α7-nAChR agonistfor the treatment (whether therapeutic or prophylactic), prevention ordelay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound selected from the Group P3.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR agonist; wherein saidα7-nAChR agonist is a compound of formula (I).

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR agonist; wherein saidα7-nAChR agonist is a compound selected from the Group P1.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR agonist; wherein saidα7-nAChR agonist is a compound selected from the Group P2.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR agonist; wherein saidα7-nAChR agonist is a compound selected from the Group P3.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises (i) diagnosing dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in said subject and(ii) administering to said subject a therapeutically effective amount ofa α7-nAChR; wherein said α7-nAChR agonist is a compound of formula (I).

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises (i) diagnosing dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in said subject and(ii) administering to said subject a therapeutically effective amount ofa α7-nAChR; wherein said α7-nAChR agonist is a compound selected fromthe Group P1.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises (i) diagnosing dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in said subject and(ii) administering to said subject a therapeutically effective amount ofa α7-nAChR; wherein said α7-nAChR agonist is a compound selected fromthe Group P2.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises (i) diagnosing dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in said subject and(ii) administering to said subject a therapeutically effective amount ofa α7-nAChR; wherein said α7-nAChR agonist is a compound selected fromthe Group P3.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a α7-nAChR agonist for the treatment, preventionor delay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound of formula (I).

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a α7-nAChR agonist for the treatment, preventionor delay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound selected from the Group P1.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a α7-nAChR agonist for the treatment, preventionor delay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound selected from the Group P2.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a α7-nAChR agonist for the treatment, preventionor delay of progression of dyskinesia associated with dopamine agonisttherapy in Parkinson's Disease; wherein said α7-nAChR agonist is acompound selected from the Group P3.

A further aspect of the invention relates to the use of a α7-nAChRagonist for the manufacture of a medicament for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease; wherein said α7-nAChRagonist is a compound of formula (I).

A further aspect of the invention relates to the use of a α7-nAChRagonist for the manufacture of a medicament for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease; wherein said α7-nAChRagonist is a compound selected from the Group P1.

A further aspect of the invention relates to the use of a α7-nAChRagonist for the manufacture of a medicament for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease; wherein said α7-nAChRagonist is a compound selected from the Group P2.

A further aspect of the invention relates to the use of a α7-nAChRagonist for the manufacture of a medicament for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease; wherein said α7-nAChRagonist is a compound selected from the Group P3.

Nicotinic Acetylcholine Receptor Alpha 7 Positive Allosteric Modulator:

As used herein a “α7-nAChR positive allosteric modulator” is a compoundthat binds to a receptor comprising a α7-nAChR subunit in vivo and invitro and is potentiating the activation of the receptor when itsphysiological ligand (i.e. acetylcholine) is binding. Potentiation canbe measured by the method disclosed in WO2001/85727, i.e. a functionalaffinity assay at the homomeric alpha 7 nicotinic acetylcholine receptor(α7 nAChR) carried out with a rat pituitary cell line stably expressingthe α7 nAChR. As read out, the calcium influx upon stimulation of thereceptor compared to acetylcholine-binding alone is used. “α7-nAChRpositive allosteric modulators” according to the invention typicallyinduce calcium influx of at least 200% of the maximal influx evoked byacetylcholine with an EC₅₀ value of at least 5000 nM; preferred agonistsinduce calcium influx of at least 300% of the maximal influx evoked byacetylcholine with an EC₅₀ value of at least 1000 nM; more preferredagonists induce calcium influx of at least 400% of the maximal influxevoked by epibatidine with an EC₅₀ value of at least 500 nM.

In particular, preferred α7-nAChR positive allosteric modulators shouldbe well absorbed from the gastrointestinal tract, should be sufficientlymetabolically stable and possess favorable pharmacokinetic properties.

Further preferred α7-nAChR positive allosteric modulators bind in-vivopotently to α7-nAChRs whilst showing little affinity for otherreceptors, especially for other nAChRs, e.g. α4β2 nAChR, for muscarinicacetylcholine receptors, e.g. M1, and/or the 5-HT₃ receptor. Furtherpreferred α7-nAChR positive allosteric modulators cross the blood brainbarrier effectively.

Preferred α7-nAChR positive allosteric modulators should be non-toxicand demonstrate few side-effects.

Furthermore, a preferred α7-nAChR positive allosteric modulator will beable to exist in a physical form that is stable, non-hygroscopic andeasily formulated.

In one embodiment, the α7-nAChR positive allosteric modulator isselective for a receptor comprising a α7-nAChR subunit, since such apositive allosteric modulator would be expected to cause fewer sideeffects than a non-selective positive allosteric modulator to a treatedsubject. A positive allosteric modulator being selective for a receptorcomprising a α7-nAChR subunit has a functional affinity to such areceptor to a much higher degree, e.g. at least 10-fold affinitydifference in EC₅₀ value, preferably at least 20-fold, more preferablyat least 50-fold, compared to any other nicotinic acetylcholinereceptor. To assess the affinity of the α7-nAChR positive allostericmodulator of the invention on other nicotinic acetylcholine receptors,the method disclosed in WO2001/85727 can be used, i.e. to assess theaffinity on human neuronal α4β2 nAChR, a similar functional assay iscarried out using a human embryonic kidney cell line stable expressingthe human α4β2 subtype and to assess the activity of the compounds ofthe invention on the “ganglionic subtype” and the “muscle type” ofnicotinic receptor, similar functional assays are carried out with ahuman embryonic kidney cell line stably expressing the human “ganglionicsubtype” or a cell line endogenously expressing the human “muscle type”of nicotinic receptors.

In the last 12 years much effort has been focused on developingselective α7 nAChR positive allosteric modulators leading to thediscovery of many different chemotypes displaying said selectiveactivity. These efforts are summarized the review from Haydar et al(Current Topics in Medicinal Chemistry, 2010, 10, 144-152), whichdescribes 11 compounds acting as α7 nAChR positive allosteric modulatorsbelonging to seven different chemical families; i.e. XY-4083;PNU-120596, PHA-758454 and NS-1738; PHA-709829; SB-206553; LY-2087101,LY-1078733 and LY-2087133; compound 26; and A-867744 (compounddesignations taken from Haydar et al). All said 11 compounds describedin Haydar et al are incorporated herein by reference. In fact, at leastone drug candidate having an α7 nAChR positive allosteric modulator modeof action obtained permission from the U.S. Food and Drug Administrationto conduct clinical testing (i.e. XY-4083).

In one embodiment, the α7-nAChR positive allosteric modulator is acompound selected from the Group P4; Group P4 is the group consisting ofcompounds

-   F-1:    (Z)—N-(4-Chloro-phenyl)-3-(4-chloro-phenylamino)-2-(3-methyl-isoxazol-5-yl)-acrylamide    (XY-4083);-   F-2:    1-(5-Chloro-2,4-dimethoxy-phenyl)-3-(5-methyl-isoxazol-3-yl)-urea    (PNU-120596);-   F-3:    1-(5-Fluoro-2,4-dimethoxy-phenyl)-3-(5-trifluoromethyl-isoxazol-3-yl)-urea    (PHA-758454);-   F-4:    1-(5-Chloro-2-hydroxy-phenyl)-3-(2-chloro-5-trifluoromethyl-phenyl)-urea    (NS-1738);-   F-5:    4-(4-Chloro-phenyl)-2-(4-methoxy-phenyl)-5-methyl-2H-pyrazol-3-ylamine    (PHA-709829);-   F-6: 5-Methyl-3,5-dihydro-2H-pyrrolo[2,3-f]indole-1-carboxylic acid    pyridin-3-ylamide (SB-206553);-   F-7:    [2-(4-Fluoro-phenylamino)-4-methyl-thiazol-5-yl]-thiophen-3-yl-methanone    (LY-2087101);-   F-8:    [2-(4-Fluoro-phenylamino)-4-methyl-thiazol-5-yl]-p-tolyl-methanone    (LY-1078733);-   F-9:    Benzo[1,3]dioxol-5-yl-[2-(4-fluoro-phenylamino)-4-methyl-thiazol-5-yl]-methanone    (LY-2087133);-   F-10:    4-Naphthalen-1-yl-3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline-8-sulfonic    acid amide; and-   F-11:    4-[5-(4-Chloro-phenyl)-2-methyl-3-propionyl-pyrrol-1-yl]-benzenesulfonamide    (A-867744);

wherein said compound is in free base form or in acid addition saltform.

A further aspect of the invention concerns the use of a α7-nAChRpositive allosteric modulator for the treatment (whether therapeutic orprophylactic), prevention or delay of progression of dyskinesiaassociated with dopamine agonist therapy in Parkinson's Disease; whereinsaid α7-nAChR positive allosteric modulator is a compound selected fromthe Group P4.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises administering to said subject atherapeutically effective amount of a α7-nAChR positive allostericmodulator; wherein said α7-nAChR positive allosteric modulator is acompound selected from the Group P4.

A further aspect of the invention relates to a method for the treatment,prevention or delay of progression of dyskinesia associated withdopamine agonist therapy in Parkinson's Disease in a subject in need ofsuch treatment, which comprises (i) diagnosing dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease in said subject and(ii) administering to said subject a therapeutically effective amount ofa α7-nAChR positive allosteric modulator; wherein said α7-nAChR positiveallosteric modulator is a compound selected from the Group P4.

A further aspect of the invention relates to a pharmaceuticalcomposition comprising a α7-nAChR positive allosteric modulator for thetreatment, prevention or delay of progression of dyskinesia associatedwith dopamine agonist therapy in Parkinson's Disease; wherein saidα7-nAChR positive allosteric modulator is a compound selected from theGroup P4.

A further aspect of the invention relates to the use of a α7-nAChRpositive allosteric modulator for the manufacture of a medicament forthe treatment, prevention or delay of progression of dyskinesiaassociated with dopamine agonist therapy in Parkinson's Disease; whereinsaid α7-nAChR positive allosteric modulator is a compound selected fromthe Group P4.

The acid addition salt of α7-nAChR agonists or α7-nAChR positiveallosteric modulators are preferably pharmaceutically acceptable salts.Such salts are known in the field (e.g. S. M. Berge, et al,“Pharmaceutical Salts”, J. Pharm. Sd., 1977, 66:1-19; and “Handbook ofPharmaceutical Salts, Properties, Selection, and Use”, Stahl, R H.,Wermuth, C. G., Eds.; Wiley-VCH and VHCA: Zurich, 2002). A“pharmaceutically acceptable salt” is intended to mean a salt of a freebase of a α7-nAChR agonist or α7-nAChR positive allosteric modulatorthat is not toxic, biologically intolerable, or otherwise biologicallyundesirable. Preferred pharmaceutically acceptable salts are those thatare pharmacologically effective and suitable for contact with thetissues of patients without undue toxicity, irritation, or allergicresponse.

Dyskinesia Associated with Dopamine agonist Therapy:

“Dopamine agonist therapy” is generally used in the treatment ofParkinson's Disease. The term “dopamine agonist therapy” as used herein,unless indicated otherwise, means any therapy that increases dopaminereceptor stimulation, including, but not limited to, therapies thatdirectly stimulate dopamine receptors (such as administration ofbromocriptine) and therapies that increase the levels of dopamine (suchas administration of levodopa or of drugs which inhibit dopaminemetabolism).

Dopamine agonist therapies include, but are not limited to, therapieswhich comprise the administration of one or more of the followingagents:

levodopa (or L-dopa being a precursor of dopamine);

levodopa in combination with a levodopa decarboxylase inhibitor, such ascarbidopa or benserazide;

levodopa in combination with a catechol-O-methyl transferase inhibitor,such as tolcapone or entacapone;

a monoamine oxidase B-inhibitor, such as selegiline or rasagiline;

a dopamine receptor agonist, such as bromocriptine, pergolide,pramipexole, ropinirole, cabergoline, apomorphine or lisuride.

The term “dopamine agonist” as used herein, unless otherwise indicated,means any agent that increases dopamine receptor stimulation. Preferreddopamine agonists are levodopa; levodopa in combination with a levodopadecarboxylase inhibitor; levodopa in combination with acatechol-O-methyl transferase inhibitor; a monoamine oxidase B-inhibitorand a dopamine receptor agonist.

In one embodiment of the invention, the therapy comprises theadministration of levodopa. Due to prevalence of associated dyskinesia,the daily dosage of levodopa for an effective dopamine agonist therapyof Parkinson's Disease needs to be determined for each patientindividually and ranges typically from 250 to 1500 mg. Said total dailydose is distributed between 2-6 administrations per day, e.g. 3-6administrations of 50-100 mg per administration. Usually, the dailydosage of levodopa needed for an effective therapy increases during thecourse of the therapy.

In one embodiment of the invention, the therapy comprises theadministration of levodopa in combination with a levodopa decarboxylaseinhibitor, such as carbidopa or benserazide.

The term “dyskinesia associated with dopamine agonist therapy”, as usedherein, unless otherwise indicated, means any dyskinesia whichaccompanies, or follows in the course of, dopamine agonist therapy, orwhich is caused by, related to, or exacerbated by dopamine agonisttherapy, wherein dyskinesia and dopamine agonist therapy are as definedabove. Such dyskinesia often, although not exclusively, occurs as aside-effect of said dopamine agonist therapies of Parkinson's Disease.

Characteristics of such dyskinesias include motor impairment, e.g. theappearance of slow and uncoordinated involuntary movements, shaking,stiffness and problems walking.

For example, patients treated with levodopa often have reduced symptomsof Parkinson's disease but they experience increasing difficulties toremain standing or even sitting. After prolonged use of levodopa, amajority of patients develop such dyskinesia. Dyskinesia can occur atany time during the cycle of treatment with levodopa.

In one embodiment, the α7-nAChR agonists or α7-nAChR positive allostericmodulators are for the treatment of dyskinesia, wherein the therapycomprises administration of levodopa, and said dyskinesia occurs at thetime of peak levodopa plasma concentrations in the patient.

In one embodiment, the α7-nAChR agonists or α7-nAChR positive allostericmodulators are for the treatment of dyskinesia, wherein the therapycomprises administration of levodopa, and said dyskinesia occurs whenthe levodopa plasma concentrations in a patient rise or fall (diphasicdyskinesia).

Surprisingly it was found that α7-nAChR agonists and/or positiveallosteric modulators are able to prolong the action of dopamineagonists, e.g. levodopa. Consequently, compared to therapies using suchdopamine agonists, the time interval for administration of said dopamineagonists may be prolonged leading to a lower daily dosage needed toachieve equal control of Parkinson's Disease.

A further aspect of the invention relates to a method for the treatmentor delay of progression of Parkinson's Disease in a subject in need ofsuch treatment, which comprises administering to said subject atherapeutically effective amount of (i) a dopamine agonist and (ii) aα7-nAChR agonist or a α7-nAChR positive allosteric modulator,

wherein the daily dosage of the dopamine agonist is reduced compared tothe daily dosage of said dopamine agonist needed to reach an equalcontrol of Parkinson's Disease in the subject without co-administrationof the α7-nAChR agonist or the α7-nAChR positive allosteric modulator.

In a preferred embodiment, said dopamine agonist comprises levodopa.

In a further preferred embodiment, said reduced daily dosage is a dosagereduced by at least 10%.

In a further preferred embodiment, said reduced daily dosage is a dosagereduced by at least 20%.

In a further preferred embodiment, said reduced daily dosage is achievedby administering the dopamine agonist in larger time intervals.

Treatment may comprise a reduction in the characteristics associatedwith dyskinesia, including for example, although not limited to, areduction in the scale of involuntary movements, a reduction in thenumber of involuntary movements, an improvement in the ability to carryout normal tasks, an improved ability to walk, increased period of timebetween episodes of dyskinesia.

One aspect of the treatment of dyskinesias associated with dopamineagonist therapy in Parkinson's Disease is that said treatment shouldhave a minimal adverse effect on the treatment of Parkinson's Diseaseitself, which is effected by the dopamine agonist therapy.

For example: neuroleptics, which can be used to treat dyskinesias, havean adverse effect on the efficiency of the dopamine agonist therapy, forexample in parameters associated with cognition, depression and sleepbehavior of Parkinson's Disease patients. Highly relevant would be ananti-dyskinetic agent that has a positive effect on the treatment ofParkinson's Disease itself, e.g. improving parameters associated withcognition.

In the case of prophylactic treatment, the α7-nAChR agonists or α7-nAChRpositive allosteric modulators may be used to delay or prevent the onsetof dyskinesia.

The term “subject” as used herein refers preferably to a human being,especially to a patient being diagnosed with Parkinson's Disease.

The term “therapeutically effective amount” as used herein typicallyrefers to a drug amount which, when administered to a subject, issufficient to provide a therapeutic benefit, e.g. is sufficient fortreating, preventing or delaying the progression of dyskinesiasassociated with dopamine agonist therapy (e.g. the amount provides anamelioration of symptoms, e.g. it leads to a reduction in the scale ofinvoluntary movements).

For the above-mentioned indications (the conditions and disorders) theappropriate dosage will vary depending upon, for example, the compoundemployed, the host, the mode of administration and the nature andseverity of the condition being treated. However, in general,satisfactory results in animals are indicated to be obtained at a dailydosage of from about 0.01 to about 100 mg/kg body weight, preferablyfrom about 0.1 to about 10 mg/kg body weight, e.g. 1 mg/kg. In largermammals, for example humans, an indicated daily dosage is in the rangefrom about 0.1 to about 1000 mg, preferably from about 1 to about 400mg, most preferably from about 3 to about 100 mg of a α7-nAChR agonistor a α7-nAChR positive allosteric modulator conveniently administered,for example, in divided doses up to four times a day.

Pharmaceutical Compositions:

For use according to the invention, the α7-nAChR agonist or α7-nAChRpositive allosteric modulator may be administered as single active agentor in combination with other active agents, in any usual manner, e.g.orally, for example in the form of tablets or capsules, parenterally,for example in the form of injection solutions or suspensions, ortransdermally, for example in the form of a patch.

In one embodiment, the manner of administration is oral administration,for example in the form of tablets or capsules.

In one embodiment, the manner of administration is transdermaladministration, for example in the form of a patch.

Moreover, the present invention provides a pharmaceutical compositioncomprising a α7-nAChR agonist or α7-nAChR positive allosteric modulatorin association with at least one pharmaceutical carrier or diluent forthe treatment, prevention or delay of progression of dyskinesiaassociated with dopamine agonist therapy in Parkinson's Disease. Suchcompositions may be manufactured in conventional manner. Unit dosageforms may contain, for example, from about 2.5 to about 25 mg of one ormore of the α7-nAChR agonist or α7-nAChR positive allosteric modulator.

The pharmaceutical compositions according to the invention arecompositions for enteral, such as nasal, rectal or oral; parenteral,such as intramuscular or intravenous; or transdermal (e.g. by a patch)administration to warm-blooded animals (human beings and animals) thatcomprise an effective dose of the pharmacological active ingredientalone or together with a significant amount of a pharmaceuticallyacceptable carrier. The dose of the active ingredient depends on thespecies of warm-blooded animal, body weight, age and individualcondition, individual pharmacokinetic data, the disease to be treatedand the mode of administration.

The pharmaceutical compositions comprise from approximately 1% toapproximately 95%, preferably from approximately 20% to approximately90%, active ingredient. Pharmaceutical compositions according to theinvention may be, for example, in unit dose form, such as in the form ofampoules, vials, suppositories, dragées, tablets or capsules.

The pharmaceutical compositions of the present invention are prepared ina manner known per se, for example by means of conventional dissolving,lyophilizing, mixing, granulating or confectioning processes. Suchprocesses are exemplified in WO 2005/079802, WO 2003/047581, WO2004/000316, WO 2005/044265, WO 2005/044266, WO 2005/044267, WO2006/114262 and WO 2007/071358.

Compositions for transdermal administration are described in Remington'sPharmaceutical Sciences 16^(th) Edition Mack; Sucker, Fuchs and Spieser,Pharmazeutische Technologie, 1^(st) Edition, Springer.

Combinations:

The invention also provides a combination comprising (A) a α7-nAChRagonist or α7-nAChR positive allosteric modulator; and

(B) at least one of levodopa, a levodopa decarboxylase inhibitor, acatechol-O-methyl transferase inhibitor, a monoamine oxidase B-inhibitoror a dopamine receptor agonist.

A further aspect of the invention concerns a combination comprising (A)a α7-nAChR agonist; and (B) at least one of levodopa, a levodopadecarboxylase inhibitor, a catechol-O-methyl transferase inhibitor, amonoamine oxidase B-inhibitor or a dopamine receptor agonist; whereinsaid α7-nAChR agonist is a compound of formula (I).

A further aspect of the invention concerns a combination comprising (A)a α7-nAChR agonist; and (B) at least one of levodopa, a levodopadecarboxylase inhibitor, a catechol-O-methyl transferase inhibitor, amonoamine oxidase B-inhibitor or a dopamine receptor agonist; whereinsaid α7-nAChR agonist is a compound selected from the Group P1.

A further aspect of the invention concerns a combination comprising (A)a α7-nAChR agonist; and (B) at least one of levodopa, a levodopadecarboxylase inhibitor, a catechol-O-methyl transferase inhibitor, amonoamine oxidase B-inhibitor or a dopamine receptor agonist; whereinsaid α7-nAChR agonist is a compound selected from the Group P2.

A further aspect of the invention concerns a combination comprising (A)a α7-nAChR agonist; and (B) at least one of levodopa, a levodopadecarboxylase inhibitor, a catechol-O-methyl transferase inhibitor, amonoamine oxidase B-inhibitor or a dopamine receptor agonist; whereinsaid α7-nAChR agonist is a compound selected from the Group P3.

Preferably, the combination is a pharmaceutical composition or acombined pharmaceutical preparation.

In this pharmaceutical composition, the combination partners i.e.

(A) the α7-nAChR agonist or the α7-nAChR positive allosteric modulator,and

(B) at least one of

i) levodopa, or

ii) a dopa decarboxylase inhibitor, or

iii) a catechol-O-methyl transferase inhibitor, or

iv) a monoamine oxidase B-inhibitor, or

iv) a dopamine agonist

can be administered together, one after the other or separately in onecombined unit dosage form or in two separate unit dosage forms. The unitdosage form may also be a fixed combination.

As used herein, the term “combinations” shall be taken to mean one ormore substances which can be administered together, one after the otheror separately in one combined unit dosage form or in two separate unitdosage forms.

Administration of the dosage forms may be co-cominantly, simultaneously,part-simultaneously, separately or sequentially. The dosage forms of thecombination may not necessarily be of the same dosage form and maycomprise one or more of:

Enteral: Oral (capsule, tablet, solution), Rectal (suppository)

Parenteral: Intravenous injection, subcutaneous injection, intramuscularinjection, intraperitoneal injection, intramammary injection

Respiratory: Inhalation, Intranasal, Intratracheal

Topical: Mucous membrane application, skin application.

In addition, the release profiles of the medicaments may not be thesame, for example one or more component of the combination may be ofextended release form.

In one embodiment of the invention a specific combination is used. Saidcombination comprises:

(A) a α7-nAChR agonist or a α7-nAChR positive allosteric modulator; and

(B) at least one active agent selected from the group consisting oflevodopa, carbidopa, benserazide tolcapone, entacapone, bromocriptine,pergolide, pramipexole, ropinirole, cabergoline, apomorphine andlisuride.

A further aspect of the invention concerns a combination comprising: (A)a α7-nAChR agonist; and (B) at least one active agent selected from thegroup consisting of levodopa, carbidopa, benserazide tolcapone,entacapone, bromocriptine, pergolide, pramipexole, ropinirole,cabergoline, apomorphine and lisuride; wherein said α7-nAChR agonist isa compound of formula (I).

A further aspect of the invention concerns a combination comprising: (A)a α7-nAChR agonist; and (B) at least one active agent selected from thegroup consisting of levodopa, carbidopa, benserazide tolcapone,entacapone, bromocriptine, pergolide, pramipexole, ropinirole,cabergoline, apomorphine and lisuride; wherein said α7-nAChR agonist isa compound selected from the Group P1.

A further aspect of the invention concerns a combination comprising: (A)a α7-nAChR agonist; and (B) at least one active agent selected from thegroup consisting of levodopa, carbidopa, benserazide tolcapone,entacapone, bromocriptine, pergolide, pramipexole, ropinirole,cabergoline, apomorphine and lisuride; wherein said α7-nAChR agonist isa compound selected from the Group P2.

A further aspect of the invention concerns a combination comprising: (A)a α7-nAChR agonist; and (B) at least one active agent selected from thegroup consisting of levodopa, carbidopa, benserazide tolcapone,entacapone, bromocriptine, pergolide, pramipexole, ropinirole,cabergoline, apomorphine and lisuride; wherein said α7-nAChR agonist isa compound selected from the Group P3.

In one embodiment of the invention a specific combination is used. Saidcombination comprises:

(A) a α7-nAChR agonist or a α7-nAChR positive allosteric modulator; and

(B) levodopa and at least one active agent selected from the groupconsisting of carbidopa, benserazide tolcapone, entacapone,bromocriptine, pergolide, pramipexole, ropinirole, cabergoline,apomorphine or lisuride.

An example of said embodiment is a combination of a α7-nAChR agonist ora α7-nAChR positive allosteric modulator with levodopa which may furthercomprise a levodopa decarboxylase inhibitor, such as carbidopa orbenserazide.

An example of said embodiment is a combination of a α7-nAChR agonistselected from the Group P3 with levodopa which further comprises alevodopa decarboxylase inhibitor, such as carbidopa.

An example of said embodiment is a combination of a α7-nAChR agonistselected from the Group P3 with levodopa which further comprises alevodopa decarboxylase inhibitor, such as benserazide.

In one embodiment of the invention a specific combination is used. Saidcombination comprises:

(A) a α7-nAChR agonist or a α7-nAChR positive allosteric modulator; and

(B) levodopa; carbidopa and entacapone.

An example of said embodiment is a combination of a α7-nAChR agonist ora α7-nAChR positive allosteric modulator with STALEVO® (levodopa;carbidopa and entacapone).

An example of said embodiment is a combination of a α7-nAChR agonistselected from the Group P3 with STALEVO® (levodopa; carbidopa andentacapone).

The invention also provides a product, for example a kit, comprising aα7-nAChR agonist or α7-nAChR positive allosteric modulator and levodopaas a combined preparation for simultaneous, separate or sequential usein therapy. The product may further comprise a levodopa decarboxylaseinhibitor, such as carbidopa or benserazide.

The usefulness of the α7-nAChR agonists or α7-nAChR positive allostericmodulators in the treatment of the above-mentioned disorders can beconfirmed in a range of standard tests including those indicated below.

1. In-Vitro Tests

1.1. Selectivity of Selected α7-nAChR Agonists Against α4β2-nAChR

Based on the activity/selectivity data shown below it is concluded thatsaid compounds are selective agonists at the α7-nAChR.

α7-nAChR activity Efficacy Potency compared to α4β2-nAChR activity EC₅₀epibatidine IC₅₀ EC₅₀ fold Compound (nM) (100%) (nM) (nM) selectivityA-1 100 83 23442 >100 000 234 C-1 24 84 9333 >100 000 388 B-13 13 894217 >100 000 324

Assay:

To assess α7-nAChR activity, a functional assay was employed using GH3cells that recombinantly expressed human α7-nAChR. 50000 cells per wellwere seeded 72 h prior to the experiment on black 96-well plates(Costar) and incubated at 37° C. in a humidified atmosphere (5% CO₂/95%air). On the day of the experiment, medium was removed by flicking theplates and replaced with 100 μl growth medium containing 2 mM Fluo-4,(Molecular Probes) in the presence of 2.5 mM probenecid (Sigma). Thecells were incubated at 37° C. in a humidified atmosphere (5% CO2/95%air) for 1 h. Plates were flicked to remove excess of Fluo-4, washedtwice with Hepes-buffered salt solution (in mM: NaCl 130, KCl 5.4, CaCl22, MgSO4 0.8, NaH2PO4 0.9, glucose 25, Hepes 20, pH 7.4; HBS) andrefilled with 100 μl of HBS containing antagonist when appropriate. Theincubation in the presence of the antagonist lasted 3-5 minutes. Plateswere placed in the cell plate stage of a FLIPR device (fluorescentimaging plate reader, Molecular Devices, Sunnyvale, Calif., USA). Afterrecording of the baseline (laser: excitation 488 nm at 1 W, CCD cameraopening of 0.4 seconds) the agonists (50 μl) were added to the cellplate using the FLIPR 96-tip pipettor while simultaneously recording thefluorescence. Calcium kinetic data were normalized to the maximal fittedresponse induced by epibatidine, which is a full agonist at α7-nAChR.Four parameter Hill equations were fitted to the concentration-response.Values of Emax (maximal effect in % compared to the epibatidineresponse) and EC50 (concentration producing half the maximal effect inμM) were derived from this fit.

Assay described in: D Feuerbach et al, Neuropharmacology (2005), 48,215-227.

To assess the activity of the compound of the invention on the humanneuronal nAChR α4β2, a similar functional assay is carried out using ahuman epithelial cell line stably expressing the human α4β2 subtype(Michelmore et al., Naunyn-Schmiedeberg's Arch. Pharmacol. (2002) 366,235).

2. In-Vivo Preclinical Tests

2.1. Oral Bioavailability and Brain Penetration in Mice

Based on the pharmacokinetic data shown below it is concluded that thebrain concentration of said compounds in mice is beyond (or at leastequal) to the compound's EC₅₀ at the α7-nAChR for at least 4 hoursfollowing an acute oral dose of 30 μmol/kg.

Compound A-1:

Plasma Brain Ratio Time (pmoles/ (pmoles/ Brain/ Administration (hour)ml ± SD) g ± SD) plasma 30 μmol/kg p.o. 0.5 634.9 ± 261.3 706.3 ± 153.41.1 30 μmol/kg p.o. 1 684.7 ± 339.6  573.7± 109.3 0.8 30 μmol/kg p.o. 2168.2 ± 91.3  191.9 ± 34.9  1.1 30 μmol/kg p.o. 4 85.0 ± 54.3 104.6 ±39.6  1.2 30 μmol/kg p.o. 6 29.5 ± 13.8 40.5 ± 12.1 1.4 30 μmol/kg p.o.24 3.8 ± 0.6 9.1 ± 2.7 2.4

Compound B-13:

Plasma Brain Ratio Time (pmoles/ (pmoles/ Brain/ Administration (hour)ml ± SD) g ± SD) plasma 30 μmol/kg p.o. 0.25 2196 ± 397 1884 ± 291 0.8630 μmol/kg p.o. 0.5 2265 ± 419 2960 ± 706 1.31 30 μmol/kg p.o. 1 1554 ±523 2940 ± 335 1.89 30 μmol/kg p.o. 2 1172 ± 252 1260 ± 172 1.07 30μmol/kg p.o. 4  429 ± 167  379 ± 134 0.88 30 μmol/kg p.o. 8  80 ± 23  93± 30 1.17 30 μmol/kg p.o. 24 * 13 ± 4

Compound C-1:

Plasma Brain Ratio Time (pmoles/ (pmoles/ Brain/ Administration (hour)ml ± SD) g ± SD) plasma 30 μmol/kg p.o. 0.25 1601 ± 758  620 ± 221 0.3930 μmol/kg p.o. 0.5 3414 ± 956 1405 ± 539 0.41 30 μmol/kg p.o. 1 1241 ±583 1458 ± 189 1.17 30 μmol/kg p.o. 2  875 ± 261 1478 ± 259 1.69 30μmol/kg p.o. 4  762 ± 159  842 ± 187 1.11 30 μmol/kg p.o. 8 239 ± 27 362± 62 1.51 30 μmol/kg p.o. 24 * *

Assay:

Compounds were orally (30 μmol/kg) administered. Male mice (30-35 g,OF1/ICstrain) were sacrificed at indicated time points after oraladministration. Trunk-blood was collected in EDTA-containing tubes andthe brain was removed and immediately frozen on dry ice. To 100 μlplasma 10 μl internal standard (1.0 μmol of a compound with solubilityand ionization properties similar to test compounds) was added andextracted three times with 500 μl dichloromethane. The combined extractswere then dried under a stream of nitrogen and re-dissolved in 100 μlacetonitrile/water (70% acetonitrile). Brains were weighed andhomogenized in water (1:5 w/v). Two 100 μl aliquots of eachhomogenate+10 μl of internal standard (same standard as used for theplasma samples) were extracted three times with 500 μl dichloromethaneand further processed as the plasma samples. Samples were separated onBeckmann high-performance liquid chromatography equipment system with anautosampler (Gilson 233XL). A 10 min linear gradient (10-70%) ofacetonitrile containing 0.5% (v/v) formic acid was used to elute thecompounds from Nucleosil CC-125/2 C18 reversed phase (Machery&Nagel)column.

The limit of detection (LOD), defined as the lowest concentration of theextracted standard sample with a signal to noise ratio of ˜3.

2.2. Functional Read-Out in Mice (Social Recognition Test)

Based on the functional in-vivo data shown below it is concluded thatoral dosing of said compounds at relevant concentrations lead to aspecific effect associated with α7-nAChR (i.e. cognition enhancement inthe Social Recognition Test in mouse).

Reduction in time scrutinizing in % ± Dose in Compound SEM at 24 h mg/kgA-1 52 ± 4 3 C-1 51 ± 3 0.3 B-13 37 ± 7 0.3

Assay:

Social interactions between two experimental animals are influenced bytheir degree of familiarity: the better they know each other, the lesstime they spend on mutual scrutiny at each meeting. In agreement withpublished data in rats (Mondadori et al., 1993) we have observed (i)that an adult mouse shows a shortened scrutiny of a young conspecific ifthe two mice are brought together again within a short time interval(e.g. 1 hour), (ii) that this curtailment is attributable to memoryprocesses: it does not occur if the familiar young partner is replacedby a strange (unfamiliar) young mouse on the second occasion and (iii)that the adult mouse's recollection of the previously scrutinizedjuvenile partner fades with the elapsed time, i.e., after 24 h, scrutinytakes just about as long as at the first encounter. Memory enhancingagents (i.e. oxiracetam) facilitate learning to the extent that thepreviously met (familiar) partner is still remembered after 24 h,whereas in vehicle treated control animals the memory usually fadesafter less than 1 hour (Thor and Holloway, 1982) or after 2-3 hours.

Baseline-test: Pairs consisting of one adult and one young mouse wereassigned at random to the experimental and control groups. In each paironly the adult mouse was orally treated 1 hour before the trial witheither vehicle or the test compound. The duration of active contacts ofthe adult mouse with the young mouse was manually recorded over a periodof 3 min, including the following behavioural, approach-related items:sniffing, nosing, grooming, licking, pawing and playing, anogenitalexploration and orientation toward the young mouse; orientation,thereby, was defined as tip of nose of the adult mouse less thanapproximately 1 cm distant from the young mouse's body.

Re-test: Twenty-four hours after the baseline-test, the adults in eachtreatment group were confronted again with the previously encountered(familiar) partner, whereas the half of the adult animals were puttogether with the previously encountered (familiar) partner and theother half with another (unfamiliar) young mouse. Again the duration ofactive approach-behaviours was recorded during a 3-min period. Prior tore-test no oral injection was given. In the table the reduction in timescrutinizing the familiar partner at time 24 compared with the familiarpartner at time 0 minutes is given (value of zero would signify noreduction).

2.3. Assessment of Antidyskinetic Effect in Parkinsonian Primates

Based on the in-vivo data in parkinsonian primates shown below it isconcluded that compound A-1 does not delay the onset of action oflevodopa, does not lower the antiparkinsonian activity of levodopa,significantly reduces the levodopa-induced dyskinesias and significantlyincreases the duration of the antiparkinsonian activity of levodopa.

2.3.1 Method

Female ovariectomized cynomolgus monkeys (Macaca fascicularis) are usedin the assessment. The animals can be rendered parkinsonian bycontinuous infusion of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine(MPTP) until they develop a stable parkinsonian syndrome. Afterrecuperation, animals are treated daily with levodopa until clear andreproducible dyskinesias are developed.

2.3.2 Assessment

Monkeys are observed through a one-way screen window in their home cage.They are observed and scored repeatedly at baseline and after a standards.c. dose of levodopa. Locomotor activity is assessed and followed withan electronic monitoring system. Antiparkinsonian responses areevaluated by measuring the locomotor activity and a Parkinson disabilityscale (see Hadj Tahar A et al, Clin Neuropharmacol 2000; 23:195-202; andSamadi P et al, Neuropharmacology 2003; 45:954-963). Dyskinesias areclosely monitored and scored according to a dyskinesia rating scale(also described in Hadj Tahar A et al; and Samadi P et al) every 15minutes until the end of the effect. The doses of levodopa are chosen toinduce motor activation and reproducible dyskinesia but no excessiveagitation.

2.3.3 Protocol

Monkeys are observed for at least two hours following an oraladministration of vehicle. On a subsequent day, the dose of levodopaselected is tested once. The animals are observed (with measures ofparkinsonian and dyskinetic scores) for the entire duration of thelevodopa effect and are also monitored for locomotor activity. Thisprovides vehicle control values as well as levodopa antiparkinsonian anddyskinesia response data for comparison with combinations of a α7-nAChRagonist/positive allosteric modulator and levodopa. The monkeys are thentested with a α7-nAChR agonist/positive allosteric modulator incombination with a fixed dose of levodopa. A suspension for oraladministration of the α7-nAChR agonist/positive allosteric modulator isadministered before levodopa. After each dose, the animals are observed(with measures of parkinsonian and dyskinetic scores) for the entireduration of effect and monitored for locomotor activity or any change inbehavior (e.g. circling, excitement, lethargy and sleepiness).

Using this protocol, compound A-1 at a dose of 20 mg/kg was tested.Results based on five monkeys (levodopa/benserazide doses: 22.5/50 mg;65/50 mg; 30/50 mg; 35/50 mg; and 25/50 mg) are shown in FIGS. 1-4. Insaid experiments, compound A-1 reduced the Mean Dyskinesia Score (totalperiod) from 2.8 to 2.1; furthermore, compound A-1 extended the Durationof Levodopa-Response from 230 minutes to 265 minutes. Neither ElapsedTime after Levodopa Administration or extent of the antiparkinsonianactivity of Levodopa measured with the antiparkinsonian score werechanged significantly with the addition of compound A-1.

2. Clinical Testing: Improvement Trials

Clinical testing of the α7-nAChR agonist/positive allosteric modulatormay be conducted, for example, in one of the following study designs.The skilled physician may look at a number of aspects of patientbehaviors and abilities. He will realize that such studies areconsidered as guidelines and the certain aspects of the studies may bemodified and redefined depending on the circumstance and environment,for example.

2.1 Trial A: Normal Patient Population

A patient population, with a normal control is dosed once a day for aweek or longer tested. The test is designed to allow for improvement,i.e. that there is a measurable parameter increase of the impairedfunction The patients are tested at the beginning and at the end of thedosage period and the results are compared and analyzed.

2.2 Trial B: Deficit Population

A patient population with a deficit associated with Parkinson's Diseaseand associated disorders e.g. Parkinson's dyskinesia, for example,Parkinson's Disease levodopa induced Parkinson's dyskinesia is dosedonce a day for a week or longer and tested. The test is designed toallow for improvement, I.e. that there is a measurable parameterincrease of the impaired function. The patients are tested at thebeginning and at the end of the dosage period and the results arecompared and analyzed.

2.3 Considerations for Designing a Trial

-   -   When designing a trial, the skilled person will appreciate the        need to protect both against floor and ceiling effects. In other        words, the study designing should allow cognition to the        measurably raised or lowered.    -   Conditions that artificially impair a function, e.g. cognition,        are one way to test enhancement of that function. Such        conditions are, for example, sleep deprivation and        pharmacological challenges.    -   Placebo control is required for all trials.    -   In assessing the data, evaluation of the likelihood of learning        and practice effects from repeat assessments must be made. The        likelihood of such effects contaminating the data to produce        false positives should be taken in to account when designing the        test, e.g. the tests should not be identical (e.g. commit the        same list of words to memory) but designed to study the same        mechanism. Other countermeasures may include single testing at        the end of a trial only.

DESCRIPTION OF FIGURES

FIG. 1: Elapsed time after L-dopa administration for behaviouralresponse in parkinsonian primates

FIG. 2: Mean Parkinsonian Score (total period) after L-dopaadministration in parkinsonian primates

FIG. 3: Mean Dyskinesia Score (total period) after L-dopa administrationin parkinsonian primates

FIG. 4: Duration of L-dopa response after L-dopa administration inparkinsonian primates

The invention claimed is:
 1. A method for the treatment or delay ofprogression of dyskinesia associated with dopamine agonist therapy inParkinson's Disease in a subject in need of such treatment, comprising:administering to said subject a therapeutically effective amount of(R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in freebase form or in acid addition salt form.
 2. The method according toclaim 1, further comprising administering levodopa.
 3. The methodaccording to claim 2, wherein the levodopa is administered in an amountthat is reduced by at least 10% relative to a daily dosage of 250-1500mg/day that would be effective for treating a patient not beingadministered the(R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane.
 4. Themethod according to claim 2, wherein the levodopa is administered in anamount that is reduced by at least 20% relative to a daily dosage of250-1500 mg/day that would be effective for treating a patient not beingadministered the(R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane.
 5. Amethod for the treatment or delay of progression of dyskinesiaassociated with dopamine agonist therapy in Parkinson's Disease in asubject in need of such treatment, comprising administering to saidsubject: a therapeutically effective amount of(R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane in freebase form or in acid addition salt form; and levodopa, wherein thelevodopa is administered in an amount that is reduced by at least 10%relative to a daily dosage of 250-1500 mg/day that would be effectivefor treating a patient not being administered the therapeuticallyeffective amount of(R)-3-(6-p-tolyl-pyridin-3-yloxy)-1-aza-bicyclo[2.2.2]octane.